Of the estimated 55 million Pap smears performed each year in the United States, more than 5% are reported as abnormal (ALTS study 2003). An estimated 800,000 women each year present with low-grade squamous intraepithelial lesions (LSIL) (Jones, BA, Davey DD. Quality management in gynaecologic cytology using interlaboratory comparison. Arch Pathol Lab Med 2000; 124(5):672-81).
These lesions will either progress with time to CIN 2-3 or invasive cancer, especially in women that present with the high-risk HPV-subtype, or regress with time in the absence of treatment. Of women diagnosed with LSIL, 25% will progress to cervical intraepithelial neoplasia (CIN) grade 2 or 3, 22-32% will have persistent CIN 1 and approximately 50%-70% will experience spontaneous regression of LSIL within 2 years (ALTS group 2003, Östör AG Natural history of cervical intraepithelial neoplasia: a critical review. Int. J. Gynecol Pathol 1993; 12:186-92). Approximately 75% will experience spontaneous regression within 5 years.
The cytologic LSIL definition of the Bethesda System is different from the Munich classification system used in Germany and throughout the EU. LSIL corresponds to condyloma or CIN 1 in the Bethesda System. In the Munich classification these findings are represented in the Pap groups II W-III D. However, it should be noted that in group III D also patients with colposcopic diagnosis of CIN 2 (moderate dysplasia) are included.
At present, there is no immediate therapy available for women with HPV presenting with LSIL. Once a low-grade abnormal Pap smear has been detected, the patient and the clinician are left with the choice of either repeating it one or more times, or proceeding to colposcopy. Colposcopy is often accompanied by biopsy. Based on the findings of the colposcopy and biopsy, treatment options include conization, cryotherapy or laser treatment. Women who have undergone such treatment options may carry an increased risk of abortion and premature labor.
There are a number of clinical trials that have been published that describe interferons to be effective against a variety of HPV cervical infections. Studies on the use of interferons for the treatment of cervical intraepitehial neoplasia report cure rates between 0-100%. These variations most likely reflect differences in dosage, duration of treatment, mode of application, study design, severity of disease, and measures of efficacy.
In an open study, Penna et al. (1994) (Penna C, Fallan MG, Gordigiani R et al., Intralesional beta-interferon treatment of cervical intraepithelial neoplasia associated with human papillomavirus infection, Tumori 1994; 80:146-150) reported 80% lesion regression and 51% reversion of HPV type 16/18 to normal following daily intra-perilesionally application into the cervix in women with CIN associated with HPV infection of 3 MIU of IFN beta for 3 weeks. Similarly, in an open pilot study, Katesmark et al. (1999) (Katesmark M., Coulter Smith S., Reynolds K., Lawton F. A pilot study of the efficacy and tolderability of intralesional recombinant human beta interferons in cervical intraepithelial neoplasia. Ann Acad Singapore 1999; 28(6)775-7) showed a 73% histology complete response rate of CIN when IFN was injected into the transformation zone.
Schneider et al. (1995) (Schneider A, Grubert T, Kirchmayr R, Wagner D, Papendick U, Schlunck G. Efficacy trial of topically administered Interferon gamma-1b gel in comparison to laser treatment in cervical intraepithelial neoplasia. Arch Gynecol Obstet 1995; 256:75-83) reported a 42% complete response, 42% partial response following IFN-gamma 1b gel therapy in women with CIN. In this study, patients with CIN II responded better compared with CIN III. It is also of interest to note that smokers showed a significantly lower cure rate when compared to non-smokers.
Zarcone at al. (1995) (Zarcone R., Bellini P., Cardone G., Cardone A. Treatment of cervix condylomata with alpha-IFN leucocytar. Clin Exp Obst Gyn 1995; 22(4):326-9) have reported success in a small, 12-patient study with combined intramuscular and topical alpha-IFN therapy in the treatment of CIN I and II, in HPV+ women. The administration of intramuscular doses of up to 3 MIU daily IFN for 3 weeks, combined with intravaginal application of an unspecified dose of IFN cream during the last two weeks of treatment, resulted in a complete response in 7 patients, partial response in 4 patients, and no response in 1 patient.
Syed et al. (1998) (Syed TA, Ahmadpour A. Human leukocyte derived interferon-a in hydrophilic gel for the treatment of intravaginal warts in women: a placebo-controlled, double-blind study. Intl J STD and AIDS 1998; 9:769-772) demonstrated that 16 MIU daily dose of a hydrophilic gel of interferon alpha administered intravaginally for 5 consecutive days per week over a 4-week treatment period was significantly more effective than placebo at curing vaginal warts. While these studies show that interferon therapy is effective in treating CIN associated HPV infections as measured by colposcopy confirmed by cytological and histological examination of random biopsies, none of these studies examine the HPV status post therapy.
Based on various limitations in these studies, a non-invasive therapy that could reverse the abnormal cytology during the early stages of the disease process and diminish or eradicate HPV presence would provide a significant benefit to the healthcare system and the physical and emotional well-being of many young women.